DNA methylation as a potential mediator of environmental risks in the development of childhood acute lymphoblastic leukemia

Abstract

5-year survival rate for childhood acute lymphoblastic leukemia (ALL) has risen to approximately 90%, yet the causal disease pathway is still poorly understood. Evidence suggests multiple 'hits' are required for disease progression; an initial genetic abnormality followed by additional secondary 'hits'. It is plausible that environmental influences may trigger these secondary hits, and with the peak incidence of diagnosis between 2 and 5 years of age, early life exposures are likely to be key. DNA methylation can be modified by many environmental exposures and is dramatically altered in cancers, including childhood ALL. Here we explore the potential that DNA methylation may be involved in the causal pathway toward disease by acting as a mediator between established environmental factors and childhood ALL development.

Keywords: DNA methylation; acute lymphoblastic leukemia; alcohol; birth weight; caffeine; developmental programming; environment; folate; iron; smoking.

Figure 1.. Overview of pathways by which environmental factors may influence DNA methylation.

Environment may influence DNA methylation at any time in the life course, however, critical windows exist (i.e., during early development in utero and early life known as developmental programming) whereby these factors may have a more profound influence. Environmental factors may affect DNA methylation directly (white arrows) and indirectly (grey arrows). Direct pathways include altered substrate availability, in other words, of the universal methyl donor, SAM which is a substrate used to methylate DNA; altering the expression of genes responsible for maintaining or establishing methylation patterns (i.e., DNMTs enzymes); altering other regulatory epigenetic mechanisms which influence methylation patterns. Indirect pathways include altering expression of genes responsible for substrate availability (i.e., genes involved in OCM which is responsible for the generation of SAM); altering other epigenetic factors which may influence substrate availability through further gene expression changes. Genetic factors (indicated by dashed black arrows) are also likely to affect substrate availability, gene expression and other epigenetic factors, and may interact with environment to influence DNA methylation levels. OCM: One carbon metabolism; SAM: S-adenosylmethionine.

Figure 2.. Plausible causal pathway to acute lymphoblastic leukemia: an initial genetic abnormality, followed by an alteration in DNA methylation influenced by an environmental exposure.